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Ann Thorac Surg 1995;60:1014
© 1995 The Society of Thoracic Surgeons
DR REPHAEL MOHR (Tel-Hashomer, Israel): In our experience we evaluated the effect of various stages of prebypass heparin administration and so on on platelet function with various methods, including in vitro, standard PLP aggregation, and whole blood aggregation, and we also evaluated it on the response of the blood from the patients to the extracellular matrix model as viewed by electron microscopy. In all those studies the initial platelet dysfunction observed was always after initiation of cardiopulmonary bypass and the levels of dysfunction were almost always observed when bypass temperature went down. However, whenever we measured the effect of heparin administration on platelet function with all these models, we never were able to demonstrate what you just showed us, that platelet function is in any way deranged by heparin administration. How can you explain this discrepancy?
DR KHURI: Other investigators, employing various methodologies, have also shown recently that heparin causes significant platelet dysfunction. In this study we have used a very reliable measure of in vivo platelet function, which is the ability of the platelet to produce thromboxane in response to a bleeding insult. I can only explain the discrepancy between our findings and yours on the basis of possible methodologic differences.
DR SAFUH ATTAR (Baltimore, MD): I congratulate Dr Khuri and his associates on a well-designed study.
In the early 1970s I presented a paper on the effects of heparin on platelets at the IVth International Congress on Thrombosis and Hemostasis. Aggregation was induced by heparin tested in platelet-rich plasma. The effect of heparin on platelet aggregation was found to be proportional to the concentration of heparin. We also compared the effect of intestinal heparin versus lung heparin; there was a significant increase in the aggregation of the platelets when intestinal heparin was used in comparison with the lung heparin. The reason is that heparin is a heterogeneous substance that probably has bits of intestines, spleen, and other things in it; therefore, these tissues are the ones that produce the platelet aggregation.
My questions to Dr Khuri are the following. First, did you use the platelet count as a function? The count of the platelets does not mean very much; the platelets may be functionless and yet the count may be all right. Second, what kind of heparin did you use, intestinal or lung heparin? Third, if you use a more purified heparin, will it minimize the effects of heparin on the platelets?
DR L. HENRY EDMUNDS (Philadelphia, PA): Doctor Khuri, I enjoyed your paper and I enjoyed the abstract, and I am familiar with your work with Drs Kestin and Mickelson. Heparin is a well-known agonist for platelets, but also it is a less well-known agonist for neutrophils and complement. It is certainly not an ideal anticoagulant by a long shot. Our group believes that there is an extrinsic factor that suppresses platelet function, as your group has pointed out. However, I have to ask you whether you think there is an intrinsic defect produced by cardiopulmonary bypass in platelets, as our data lead us to believe.
I am disturbed by your concluding comment, that maybe a combination of surface-bound heparin and some other anticoagulant will get us around this problem. Recombinant hirudin is the alternative anticoagulant that is being considered the most. This is a very tight-binding inhibitor of thrombin, but it does not prevent the formation of thrombin. It is important for everyone who does cardiac surgery to realize that thrombin is formed in progressively increasing amounts during every cardiopulmonary bypass operation, and that it is a dangerous enzyme to circulate. So the idea of using surface-bound heparin with a direct thrombin inhibitor such as hirudin has little appeal to me. Surface-bound heparin does not appear to have an anticoagulant effect and therefore is unlikely to help.
Would you comment on whether you believe, or your group believes, that there is an intrinsic defect in platelets produced by cardiopulmonary bypass?
DR KHURI: Thank you, Dr Edmunds. I am very appreciative of your comments. I can very well understand your concern about my remark regarding the possible advantage of combining low-dose heparin with heparin-coated circuits, and I look forward to the publication of your data which, as I interpret from your comments, will show that such a combination would not adequately prevent the formation of thrombin, which, I agree, is a molecule we need to avoid during bypass. In the present study, we maintained relatively high activated clotting time levels (an average of 700 to 800 seconds) to ensure specifically that the thrombin was adequately neutralized.
As to the question of whether the cardiopulmonary bypass--induced platelet defect is intrinsic or extrinsic to the platelet, our studies to date have identified hypothermia and heparin as extrinsic factors responsible, in part, for this platelet dysfunction. Our studies have not ruled out the presence of a cardiopulmonary bypass--induced intrinsic platelet defect. As my colleagues and I have published in Blood, however, the mechanism of this intrinsic defect is not likely to be a loss of the platelet membrane receptors GPIb and GPIIb-IIIa, as earlier studies had suggested.
Doctor Attar, we appreciate the fact that you were way ahead of your time in showing, more than 20 years ago, that heparin caused abnormal platelet aggregation. We have not used platelet aggregation in the assessment of platelet function because of the variability in that technique. Instead, we have opted for the in vivo test of measuring thromboxane B2 in the blood shed at the site of the bleeding time determination. We believe that this test of platelet function is more applicable and relevant to the patient undergoing cardiopulmonary bypass. Maybe that is why there is a discrepancy between our data and those of Dr Mohr from Israel. As to your specific questions about heparin, we have used porcine heparin, and we have had no experience with the more purified forms of heparin.
Related Article
Ann. Thorac. Surg. 1995 60: 1008-1014.
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